We have studied the effects of neurotransmitters which convey information across the plasma membrane while binding to and remaining at cell-surface receptors. In neurons cultured from the cerebellum of neonatal rats, we have shown that the ability to synthesize the second messenger cyclic GMP in response to excitatory amino acids is related to the developmental stage of the neuron, is linked to the influx of calcium ions, and is mediated by the NMDA-subtype of glutamate receptor. When this receptor is occupied by an appropriate agonist, a receptor-gated channel permits sodium and calcium influx; however, in the brain this channel is normally blocked by magnesium in a voltage-dependent manner and may only open in response to high-frequency stimulation. We have recently found that the magnesium block is sensitive to the partial depolarization resulting from reduced neuronal energy levels; decreases in adenine nucleotide levels due to glucose starvation, oxygen deprivation or metabolic poisons, cause sufficient depolarization to relieve the magnesium block of the NMDA receptor channel. Thus, when neuronal energy levels are compromised, glutamate can persistently open the channel resulting in excession influx; the increased energy demands by the pumps involved in maintaining ion gradients cannot be met in the energy- poor neurons and neuronal death ensues. Although the exact mechanism of killing is not clear, we shown a close correlation between neurotoxicity and degradation of the structural protein, fodrin, probably via the activation of calcium-dependent proteases. Our results provide experimental evidence for a mechanism which may trigger the transition of glutamate from neurotransmitter to neurotoxin; this mechanism may underlie a variety of neurological disorder. As a model system for this mechanism of neurotoxicity, cerebellar granule which may be of clinical value in preventing the neuronal damage characteristic of ischemia due to stroke or cardiac arrest and of several neurodegenerative diseases.